A role for amygdala endocannabinoid signaling in reconsolidation of cocaine-associated memories

Madalyn Hafenbreidel & Courtney A. Miller

doi : 10.1038/s41386-020-00951-x

Neuropsychopharmacology volume 46, pages1549–1550 (2021)

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Caution is advised when interpreting subgroup analyses

Klaus Munkholm & Asger Sand Paludan-Müller

doi : 10.1038/s41386-021-01025-2

Neuropsychopharmacology volume 46, page1551 (2021)

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Reply to Drs Munkholm and Paludan-Müller’s comment on our paper “Augmentation therapy with minocycline in treatment-resistant depression patients with low-grade peripheral inflammation: results from a double-blind randomised clinical trial”

Maria A. Nettis, Carmine M. Pariante & Valeria Mondelli

doi : 10.1038/s41386-021-01042-1

Neuropsychopharmacology volume 46, pages1552–1553 (2021)

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Basolateral amygdala CB1 receptors gate HPA axis activation and context-cocaine memory strength during reconsolidation

Jessica A. Higginbotham, Nicole M. Jones, Rong Wang, Robert J. Christian, Jobe L. Ritchie, Ryan J. McLaughlin & Rita A. Fuchs

doi : 10.1038/s41386-020-00919-x

Neuropsychopharmacology volume 46, pages1554–1564 (2021)

Re-exposure to a cocaine-associated context triggers craving and relapse through the retrieval of salient context-drug memories. Upon retrieval, context-drug memories become labile and temporarily sensitive to modification before they are reconsolidated into long-term memory stores. The effects of systemic cannabinoid type 1 receptor (CB1R) antagonism indicate that CB1R signaling is necessary for cocaine-memory reconsolidation and associated glutamatergic plasticity in the basolateral amygdala (BLA); however, the contribution of BLA CB1R signaling to cocaine-memory reconsolidation is unknown. Here, we assessed whether intra-BLA CB1R manipulations immediately after cocaine-memory retrieval alter cocaine-memory strength indexed by subsequent drug context-induced cocaine-seeking behavior in an instrumental rodent model of drug relapse. Administration of the CB1R antagonist, AM251 (0.3?µg/hemisphere) into the BLA increased subsequent drug context-induced cocaine-seeking behavior in a memory retrieval-dependent and anatomically selective manner. Conversely, the CB1R agonist, WIN55,212-2 (0.5 or 5?µg/hemisphere) failed to alter this behavior. In follow-up experiments, cocaine-memory retrieval elicited robust hypothalamic-pituitary-adrenal axis activation, as indicated by a rise in serum corticosterone concentrations. Intra-BLA AM251 administration during memory reconsolidation selectively increased this cocaine-memory retrieval-induced corticosterone response. Intra-BLA corticosterone administration (3 or 10?ng/hemisphere) during memory reconsolidation did not augment subsequent cocaine-seeking behavior, suggesting that CB1R-dependent effects of corticosterone on memory strength, if any, are mediated outside of the BLA. Together, these findings suggest that CB1R signaling in the BLA gates cocaine-memory strength, possibly by diminishing the impact of cue-induced arousal on the integrity of the reconsolidating memory trace or on the efficacy of the memory reconsolidation process.

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A sex-dependent role for the prelimbic cortex in impulsive action both before and following early cocaine abstinence

Travis M. Moschak & Regina M. Carelli

doi : 10.1038/s41386-021-01024-3

Neuropsychopharmacology volume 46, pages1565–1573 (2021)

Although impulsive action is strongly associated with addiction, the neural underpinnings of this relationship and how they are influenced by sex have not been well characterized. Here, we used a titrating reaction time task to assess differences in impulsive action in male and female Long Evans rats both before and after short (4–6 days) or long (25–27 days) abstinence from 2 weeks of cocaine or water/saline self-administration (6?h daily access). Neural activity in the prelimbic cortex (PrL) and nucleus accumbens (NAc) core was assessed at each time point. We found that a history of cocaine self-administration increased impulsivity in all rats following short, but not long, abstinence. Furthermore, male rats with an increased ratio of excited to inhibited neurons in the PrL at the start of each trial in the task exhibited higher impulsivity in the naïve state (before self-administration). Following short abstinence from cocaine, PrL activity in males became more inhibited, and this change in activity predicted the shift in impulsivity. However, PrL activity did not track impulsivity in female rats. Additionally, although the NAc core tracked several aspects of behavior in the task, it did not track impulsivity in either sex. Together, these findings demonstrate a sex-dependent role for the PrL in impulsivity both before and after a history of cocaine.

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Serum- and glucocorticoid-inducible kinase 1 activity in ventral tegmental area dopamine neurons regulates cocaine conditioned place preference but not cocaine self-administration

Marie A. Doyle, Vedrana Bali, Andrew L. Eagle, Ali R. Stark, Barbara Fallon, Rachael L. Neve, A. J. Robison & Michelle S. Mazei-Robison

doi : 10.1038/s41386-021-01032-3

Neuropsychopharmacology volume 46, pages1574–1583 (2021)

Drugs of abuse regulate the activity of the mesolimbic dopamine (DA) system, and drug-induced changes in ventral tegmental area (VTA) cellular activity and gene regulation are linked to behavioral outputs associated with addiction. Previous work from our lab determined that VTA serum- and glucocorticoid-inducible kinase 1 (SGK1) transcription and catalytic activity were increased by repeated cocaine administration; however, it was unknown if these biochemical changes contributed to cocaine-elicited behaviors. Using transgenic and viral-mediated manipulations, we investigated the role of VTA SGK1 catalytic activity in regulating cocaine conditioned place preference and self-administration. We showed intra-VTA infusion of a catalytically inactive SGK1 mutant (K127Q) significantly decreased cocaine conditioned place preference (CPP). Further, we found that K127Q expression in VTA DA neurons significantly decreased cocaine CPP, while this same manipulation in VTA GABA neurons had no effect. However, blunted VTA DA SGK1 catalytic activity did not alter cocaine self-administration. Altogether, these studies identify the specific VTA cells critical for SGK1-mediated effects on cocaine CPP but not self-administration.

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Quantitative standardization of resident mouse behavior for studies of aggression and social defeat

Christine C. Kwiatkowski, Hope Akaeze, Isabella Ndlebe, Nastacia Goodwin, Andrew L. Eagle, Ken Moon, Andrew R. Bender, Sam A. Golden & Alfred Jay Robison

doi : 10.1038/s41386-021-01018-1

Neuropsychopharmacology volume 46, pages1584–1593 (2021)

Territorial reactive aggression in mice is used to study the biology of aggression-related behavior and is also a critical component of procedures used to study mood disorders, such as chronic social defeat stress. However, quantifying mouse aggression in a systematic, representative, and easily adoptable way that allows direct comparison between cohorts within or between studies remains a challenge. Here, we propose a structural equation modeling approach to quantify aggression observed during the resident-intruder procedure. Using data for 658 sexually experienced CD-1 male mice generated by three research groups across three institutions over a 10-year period, we developed a higher-order confirmatory factor model wherein the combined contributions of latency to the first attack, number of attack bouts, and average attack duration on each trial day (easily observable metrics that require no specialized equipment) are used to quantify individual differences in aggression. We call our final model the Mouse Aggression Detector (MAD) model. Correlation analyses between MAD model factors estimated from multiple large datasets demonstrate generalizability of this measurement approach, and we further establish the stability of aggression scores across time within cohorts and demonstrate the utility of MAD for selecting aggressors which will generate a susceptible phenotype in social defeat experiments. Thus, this novel aggression scoring technique offers a systematic, high-throughput approach for aggressor selection in chronic social defeat stress studies and a more consistent and accurate study of mouse aggression itself.

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Striatal Shati/Nat8l–BDNF pathways determine the sensitivity to social defeat stress in mice through epigenetic regulation

Hajime Miyanishi, Shin-ichi Muramatsu & Atsumi Nitta

doi : 10.1038/s41386-021-01033-2

Neuropsychopharmacology volume 46, pages1594–1605 (2021)

The global number of patients with depression increases in correlation to exposure to social stress. Chronic stress does not trigger depression in all individuals, as some remain resilient. The underlying molecular mechanisms that contribute to stress sensitivity have been poorly understood, although revealing the regulation of stress sensitivity could help develop treatments for depression. We previously found that striatal Shati/Nat8l, an N-acetyltransferase, was increased in a depression mouse model. We investigated the roles of Shati/Nat8l in stress sensitivity in mice and found that Shati/Nat8l and brain-derived neurotrophic factor (BDNF) levels in the dorsal striatum were increased in stress-susceptible mice but not in resilient mice exposed to repeated social defeat stress (RSDS). Knockdown of Shati/Nat8l in the dorsal striatum induced resilience to RSDS. In addition, blockade of BDNF signaling in the dorsal striatum by ANA-12, a BDNF-specific receptor tropomyosin-receptor-kinase B (TrkB) inhibitor, also induced resilience to stress. Shati/Nat8l is correlated with BDNF expression after RSDS, and BDNF is downstream of Shati/Nat8l pathways in the dorsal striatum; Shati/Nat8l is epigenetically regulated by BDNF via histone acetylation. Our results demonstrate that striatal Shati/Nat8l–BDNF pathways determine stress sensitivity through epigenetic regulation. The striatal Shati/Nat8l–BDNF pathway could be a novel target for treatments of depression and could establish a novel therapeutic strategy for depression patients.

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Chronic social defeat stress impairs goal-directed behavior through dysregulation of ventral hippocampal activity in male mice

Keitaro Yoshida, Michael R. Drew, Anna Kono, Masaru Mimura, Norio Takata & Kenji F. Tanaka

doi : 10.1038/s41386-021-00990-y

Neuropsychopharmacology volume 46, pages1606–1616 (2021)

Chronic stress is a risk factor for a variety of psychiatric disorders, including depression. Although impairments to motivated behavior are a major symptom of clinical depression, little is known about the circuit mechanisms through which stress impairs motivation. Furthermore, research in animal models for depression has focused on impairments to hedonic aspects of motivation, whereas patient studies suggest that impairments to appetitive, goal-directed motivation contribute significantly to motivational impairments in depression. Here, we characterized goal-directed motivation in repeated social defeat stress (R-SDS), a well-established mouse model for depression in male mice. R-SDS impaired the ability to sustain and complete goal-directed behavior in a food-seeking operant lever-press task. Furthermore, stress-exposed mice segregated into susceptible and resilient subpopulations. Interestingly, susceptibility to stress-induced motivational impairments was unrelated to stress-induced social withdrawal, another prominent effect of R-SDS in mouse models. Based on evidence that ventral hippocampus (vHP) modulates sustainment of goal-directed behavior, we monitored vHP activity during the task using fiber photometry. Successful task completion was associated with suppression of ventral hippocampal neural activity. This suppression was diminished after R-SDS in stress-susceptible but not stress-resilient mice. The serotonin selective reuptake inhibitor (SSRI) escitalopram and ketamine both normalized vHP activity during the task and restored motivated behavior. Furthermore, optogenetic vHP inhibition was sufficient to restore motivated behavior after stress. These results identify vHP hyperactivity as a circuit mechanism of stress-induced impairments to goal-directed behavior and a putative biomarker that is sensitive to antidepressant treatments and that differentiates susceptible and resilient individuals.

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Autism risk gene KMT5B deficiency in prefrontal cortex induces synaptic dysfunction and social deficits via alterations of DNA repair and gene transcription

Zi-Jun Wang, Ben Rein, Ping Zhong, Jamal Williams, Qing Cao, Fengwei Yang, Freddy Zhang, Kaijie Ma & Zhen Yan

doi : 10.1038/s41386-021-01029-y

Neuropsychopharmacology volume 46, pages1617–1626 (2021)

Large-scale genetic screening has identified KMT5B (SUV420H1), which encodes a histone H4 K20 di- and tri-methyltransferase highly expressed in prefrontal cortex (PFC), as a top-ranking high-risk gene for autism. However, the biological function of KMT5B in the brain is poorly characterized, and how KMT5B deficiency is linked to autism remains largely unknown. Here we knocked down Kmt5b in PFC and examined behavioral and electrophysiological changes, as well as underlying molecular mechanisms. Mice with Kmt5b deficiency in PFC display social deficits, a core symptom of autism, without the alteration of other behaviors. Kmt5b deficiency also produces deficits in PFC glutamatergic synaptic transmission, which is accompanied by the reduced synaptic expression of glutamate receptor subunits and associated proteins. Kmt5b deficiency-induced reduction of H4K20me2 impairs 53BP1-mediated DNA repair, leading to the elevation of p53 expression and its target gene Ddit4 (Redd1), which is implicated in synaptic impairment. RNA-sequencing data indicate that Kmt5b deficiency results in the upregulation of genes enriched in cellular stress response and ubiquitin-dependent protein degradation. Collectively, this study has revealed the functional role of Kmt5b in the PFC, and suggests that Kmt5b deficiency could cause autistic phenotypes by inducing synaptic dysfunction and transcriptional aberration.

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Genetic underpinnings of sociability in the general population

Janita Bralten, Nina R. Mota, Cornelius J. H. M. Klemann, Ward De Witte, Emma Laing, David A. Collier, Hilde de Kluiver, Stephanie E. E. C. Bauduin, Celso Arango, Jose L. Ayuso-Mateos, Chiara Fabbri, Martien J. Kas, Nic van der Wee, Brenda W. J. H. Penninx, Alessandro Serretti, Barbara Franke & Geert Poelmans

doi : 10.1038/s41386-021-01044-z

Neuropsychopharmacology volume 46, pages1627–1634 (2021)

Levels of sociability are continuously distributed in the general population, and decreased sociability represents an early manifestation of several brain disorders. Here, we investigated the genetic underpinnings of sociability in the population. We performed a genome-wide association study (GWAS) of a sociability score based on four social functioning-related self-report questions from 342,461 adults in the UK Biobank. Subsequently we performed gene-wide and functional follow-up analyses. Robustness analyses were performed in the form of GWAS split-half validation analyses, as well as analyses excluding neuropsychiatric cases. Using genetic correlation analyses as well as polygenic risk score analyses we investigated genetic links of our sociability score to brain disorders and social behavior outcomes. Individuals with autism spectrum disorders, bipolar disorder, depression, and schizophrenia had a lower sociability score. The score was significantly heritable (SNP h2 of 6%). We identified 18 independent loci and 56 gene-wide significant genes, including genes like ARNTL, DRD2, and ELAVL2. Many associated variants are thought to have deleterious effects on gene products and our results were robust. The sociability score showed negative genetic correlations with autism spectrum, disorders, depression, schizophrenia, and two sociability-related traits—loneliness and social anxiety—but not with bipolar disorder or Alzheimer’s disease. Polygenic risk scores of our sociability GWAS were associated with social behavior outcomes within individuals with bipolar disorder and with major depressive disorder. Variation in population sociability scores has a genetic component, which is relevant to several psychiatric disorders. Our findings provide clues towards biological pathways underlying sociability.

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Neural correlates of anger expression in patients with PTSD

Neir Eshel, Adi Maron-Katz, Wei Wu, Duna Abu-Amara, Charles R. Marmar & Amit Etkin

doi : 10.1038/s41386-020-00942-y

Neuropsychopharmacology volume 46, pages1635–1642 (2021)

Anger is a common and debilitating symptom of post-traumatic stress disorder (PTSD). Although studies have identified brain circuits underlying anger experience and expression in healthy individuals, how these circuits interact with trauma remains unclear. Here, we performed the first study examining the neural correlates of anger in patients with PTSD. Using a data-driven approach with resting-state fMRI, we identified two prefrontal regions whose overall functional connectivity was inversely associated with anger: the left anterior middle frontal gyrus (aMFG) and the right orbitofrontal cortex (OFC). We then used concurrent TMS-EEG to target the left aMFG parcel previously identified through fMRI, measuring its cortical excitability and causal connectivity to downstream areas. We found that low-anger PTSD patients exhibited enhanced excitability in the left aMFG and enhanced causal connectivity between this region and visual areas. Together, our results suggest that left aMFG activity may confer protection against the development of anger, and therefore may be an intriguing target for circuit-based interventions for anger in PTSD.

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Traumatic memory reactivation with or without propranolol for PTSD and comorbid MD symptoms: a randomised clinical trial

Pascal Roullet, Guillaume Vaiva, Etienne Véry, Axel Bourcier, Antoine Yrondi, Laetitia Dupuch, Pierre Lamy, Claire Thalamas, Laurence Jasse, Wissam El Hage & Philippe Birmes

doi : 10.1038/s41386-021-00984-w

Neuropsychopharmacology volume 46, pages1643–1649 (2021)

Post-traumatic stress disorder (PTSD) is difficult to treat but one promising strategy is to block memory reconsolidation of the traumatic event. This study aimed to evaluate the efficacy of traumatic memory reactivation under the influence of propranolol, a noradrenergic beta-receptor blocker, in reducing PTSD symptoms as well as comorbid major depression (MD) symptoms. We conducted a double blind, placebo-controlled, randomised clinical trial in 66 adults diagnosed with longstanding PTSD. Propranolol or a placebo was administered 90?min before a brief memory reactivation session, once a week for 6 consecutive weeks. Measures included the SCID PTSD module, the PTSD Check List (PCL-S) and the Beck Depression Inventory-II (BDI-II). PTSD symptoms decreased both in the pre-reactivation propranolol group (39.28%) and the pre-reactivation placebo group (34.48 %). During the 6 treatment sessions, PCL-S and BDI-II scores decreased to similar extent in both groups and there were no treatment differences. During the 3-month follow-up period, there were no treatment effects for the mean PCL-S and BDI-II scores. However, in patients with severe PTSD symptoms (PCL-S???65) before treatment, PCL-S and BDI-II scores continued to decline 3 months after the end of treatment in the propranolol group while they increased in the placebo group. Repeated traumatic memory reactivation seemed to be effective for PTSD and comorbid MD symptoms. However, the efficacy of propranolol was not greater than that of placebo 1 week post treatment. Furthermore, in this traumatic memory reactivation, PTSD symptom severity at baseline might have influenced the post-treatment effect of propranolol.

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Dysregulation of threat neurociruitry during fear extinction: the role of anhedonia

Katherine S. Young, Susan Y. Bookheimer, Robin Nusslock, Richard E. Zinbarg, Katherine S. F. Damme, Iris Ka-Yi Chat, Nicholas J. Kelley, Meghan Vinograd, Marcelina Perez, Kelly Chen, Aileen Echiverri Cohen & Michelle G. Craske

doi : 10.1038/s41386-021-01003-8

Neuropsychopharmacology volume 46, pages1650–1657 (2021)

Dimensional models of anxiety and depression highlight common and distinct symptom clusters that are thought to reflect disruptions in underlying functional processes. The current study investigated how functioning of threat neurocircuitry relates to symptom dimensions of anxiety and depression. Participants were aged 18–19 years (n?=?229, 158 female) and were selected to ensure a range of scores on symptom measures. Symptom dimensions of “General Distress” (common to anxiety disorders and depression), “Fears” (more specific to anxiety disorders), and “Anhedonia-apprehension” (more specific to depression) were evaluated. Participants underwent functional magnetic resonance imaging during a Pavlovian fear conditioning paradigm. Multilevel modeling analyses estimated relationships between symptom dimensions and activation in threat neural circuitry. Exploratory whole brain analyses were also conducted. Threat-related neural activity was not associated with General Distress or Fears. Anhedonia-apprehension was associated with activation of bilateral amygdala, anterior insula and dACC during late extinction. We found no evidence to support an association between symptom dimensions of General Distress or Fears with threat circuitry activation in a large sample of young adults. We did, however, find that the symptom dimension of Anhedonia-apprehension was significantly associated with threat-related neural activation during fear extinction. This effect requires replication in future work but may reflect anhedonic impairments in learning when contingencies are altered, possibly linked to the rewarding relief of an unexpectedly absent threat.

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Incerto-thalamic modulation of fear via GABA and dopamine

Archana Venkataraman, Sarah C. Hunter, Maria Dhinojwala, Diana Ghebrezadik, JiDong Guo, Kiyoshi Inoue, Larry J. Young & Brian George Dias

doi : 10.1038/s41386-021-01006-5

Neuropsychopharmacology volume 46, pages1658–1668 (2021)

Fear generalization and deficits in extinction learning are debilitating dimensions of Post-Traumatic Stress Disorder (PTSD). Most understanding of the neurobiology underlying these dimensions comes from studies of cortical and limbic brain regions. While thalamic and subthalamic regions have been implicated in modulating fear, the potential for incerto-thalamic pathways to suppress fear generalization and rescue deficits in extinction recall remains unexplored. We first used patch-clamp electrophysiology to examine functional connections between the subthalamic zona incerta and thalamic reuniens (RE). Optogenetic stimulation of GABAergic ZI ? RE cell terminals in vitro induced inhibitory post-synaptic currents (IPSCs) in the RE. We then combined high-intensity discriminative auditory fear conditioning with cell-type-specific and projection-specific optogenetics in mice to assess functional roles of GABAergic ZI ? RE cell projections in modulating fear generalization and extinction recall. In addition, we used a similar approach to test the possibility of fear generalization and extinction recall being modulated by a smaller subset of GABAergic ZI ? RE cells, the A13 dopaminergic cell population. Optogenetic stimulation of GABAergic ZI ? RE cell terminals attenuated fear generalization and enhanced extinction recall. In contrast, optogenetic stimulation of dopaminergic ZI ? RE cell terminals had no effect on fear generalization but enhanced extinction recall in a dopamine receptor D1-dependent manner. Our findings shed new light on the neuroanatomy and neurochemistry of ZI-located cells that contribute to adaptive fear by increasing the precision and extinction of learned associations. In so doing, these data reveal novel neuroanatomical substrates that could be therapeutically targeted for treatment of PTSD.

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CPEB3-dowregulated Nr3c1 mRNA translation confers resilience to developing posttraumatic stress disorder-like behavior in fear-conditioned mice

Wen-Hsin Lu, Hsu-Wen Chao, Pei-Yi Lin, Shu-Hui Lin, Tzu-Hsien Liu, Hao-Wen Chen & Yi-Shuian Huang

doi : 10.1038/s41386-021-01017-2

Neuropsychopharmacology volume 46, pages1669–1679 (2021)

Susceptibility or resilience to posttraumatic stress disorder (PTSD) depends on one’s ability to appropriately adjust synaptic plasticity for coping with the traumatic experience. Activity-regulated mRNA translation synthesizes plasticity-related proteins to support long-term synaptic changes and memory. Hence, cytoplasmic polyadenylation element-binding protein 3-knockout (CPEB3-KO) mice, showing dysregulated translation-associated synaptic rigidity, may be susceptible to PTSD-like behavior. Here, using a context-dependent auditory fear conditioning and extinction paradigm, we found that CPEB3-KO mice exhibited traumatic intensity-dependent PTSD-like fear memory. A genome-wide screen of CPEB3-bound transcripts revealed that Nr3c1, encoding glucocorticoid receptor (GR), was translationally suppressed by CPEB3. Thus, CPEB3-KO neurons with elevated GR expression exhibited increased corticosterone-induced calcium influx and decreased mRNA and protein levels of brain-derived neurotrophic factor (Bdnf). Moreover, the reduced expression of BDNF was associated with increased GR level during fear extinction in CPEB3-KO hippocampi. Intracerebroventricular delivery of BDNF before extinction training mitigated spontaneous fear intrusion in CPEB3-KO mice during extinction recall. Analysis of two GEO datasets revealed decreased transcriptomic expression of CPEB3 but not NR3C1 in peripheral blood mononuclear cells of humans with PTSD. Collectively, this study reveals that CPEB3, as a potential PTSD-risk gene, downregulates Nr3c1 translation to maintain proper GR-BDNF signaling for fear extinction.

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Investigation of genetic loci shared between bipolar disorder and risk-taking propensity: potential implications for pharmacological interventions

Claudia Pisanu, Donatella Congiu, Giovanni Severino, Raffaella Ardau, Caterina Chillotti, Maria Del Zompo, Bernhard T. Baune & Alessio Squassina

doi : 10.1038/s41386-021-01045-y

Neuropsychopharmacology volume 46, pages1680–1692 (2021)

Patients with bipolar disorder (BD) often show increased risk-taking propensity, which may contribute to poor clinical outcome. While these two phenotypes are genetically correlated, there is scarce knowledge on the shared genetic determinants. Using GWAS datasets on BD (41,917 BD cases and 371,549 controls) and risk-taking (n?=?466,571), we dissected shared genetic determinants using conjunctional false discovery rate (conjFDR) and local genetic covariance analysis. We investigated specificity of identified targets using GWAS datasets on schizophrenia (SCZ) and attention-deficit hyperactivity disorder (ADHD). The putative functional role of identified targets was evaluated using different tools and GTEx v. 8. Target druggability was evaluated using DGIdb and enrichment for drug targets with genome for REPositioning drugs (GREP). Among 102 loci shared between BD and risk-taking, 87% showed the same direction of effect. Sixty-two were specifically shared between risk-taking propensity and BD, while the others were also shared between risk-taking propensity and either SCZ or ADHD. By leveraging pleiotropic enrichment, we reported 15 novel and specific loci associated with BD and 22 with risk-taking. Among cross-disorder genes, CACNA1C (a known target of calcium channel blockers) was significantly associated with risk-taking propensity and both BD and SCZ using conjFDR (p?=?0.001 for both) as well as local genetic covariance analysis, and predicted to be differentially expressed in the cerebellar hemisphere in an eQTL-informed gene-based analysis (BD, Z?=?7.48, p?=?3.8E?14; risk-taking: Z?=?4.66, p?=?1.6E?06). We reported for the first time shared genetic determinants between BD and risk-taking propensity. Further investigation into calcium channel blockers or development of innovative ligands of calcium channels might form the basis for innovative pharmacotherapy in patients with BD with increased risk-taking propensity.

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Dynamics of amygdala connectivity in bipolar disorders: a longitudinal study across mood states

Gwladys Rey, Thomas A. W. Bolton, Julian Gaviria, Camille Piguet, Maria Giulia Preti, Sophie Favre, Jean-Michel Aubry, Dimitri Van De Ville & Patrik Vuilleumier

doi : 10.1038/s41386-021-01038-x

Neuropsychopharmacology volume 46, pages1693–1701 (2021)

Alterations in activity and connectivity of brain circuits implicated in emotion processing and emotion regulation have been observed during resting-state for different clinical phases of bipolar disorders (BD), but longitudinal investigations across different mood states in the same patients are still rare. Furthermore, measuring dynamics of functional connectivity patterns offers a powerful method to explore changes in the brain’s intrinsic functional organization across mood states. We used a novel co-activation pattern (CAP) analysis to explore the dynamics of amygdala connectivity at rest in a cohort of 20 BD patients prospectively followed-up and scanned across distinct mood states: euthymia (20 patients; 39 sessions), depression (12 patients; 18 sessions), or mania/hypomania (14 patients; 18 sessions). We compared them to 41 healthy controls scanned once or twice (55 sessions). We characterized temporal aspects of dynamic fluctuations in amygdala connectivity over the whole brain as a function of current mood. We identified six distinct networks describing amygdala connectivity, among which an interoceptive-sensorimotor CAP exhibited more frequent occurrences during hypomania compared to other mood states, and predicted more severe symptoms of irritability and motor agitation. In contrast, a default-mode CAP exhibited more frequent occurrences during depression compared to other mood states and compared to controls, with a positive association with depression severity. Our results reveal distinctive interactions between amygdala and distributed brain networks in different mood states, and foster research on interoception and default-mode systems especially during the manic and depressive phase, respectively. Our study also demonstrates the benefits of assessing brain dynamics in BD.

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In memoriam—Stephen Hugh Koslow, Ph.D

Charles B. Nemeroff & Alan Frazer

doi : 10.1038/s41386-021-01049-8

Neuropsychopharmacology volume 46, page1702 (2021)

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